Analgesic conjugates

Abstract

The present invention relates generally to analgesic compounds having a mu opioid receptor agonist linked to a delta opioid receptor antagonist, and to methods for producing analgesia using such compounds. As compared to opioids such as morphine, these compounds can cause less tolerance, physical dependence, and/or constipation. These compounds are also more potent than morphine and are able to cross the blood brain barrier, thereby allowing for peripheral (e.g., IV) administration.

1 - 4 . (canceled) 
   
   
       5 . The method of  claim 60 , wherein administration of the conjugate causes less inhibition of gastrointestinal (GI) transit than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       6 . The method of  claim 60 , wherein administration of the conjugate causes less constipation than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       7 . (canceled) 
   
   
       8 . The method of  claim 60 , wherein administration of the conjugate causes less dependence than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       9 . The method of  claim 60 , wherein the administration of the conjugate causes less tolerance than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       10 . The method of  claim 60 , wherein the conjugate has the formula:
   R 1 —X 1 —R 2      
     wherein
 R 1  is a mu opioid receptor agonist; 
 R 2  is a delta opioid receptor antagonist; and 
 X 1  is a linker. 
 
   
   
       11 . The method of  claim 10 , wherein X 1  comprises an amino acid. 
   
   
       12 . The method of  claim 10 , wherein X 1  comprises a peptide. 
   
   
       13 . The method of  claim 10 , wherein X 1  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 10-30 carbon atoms in the chain, wherein one or more of the carbon atoms in the chain is optionally replaced by (—O—) or (—NH—). 
   
   
       14 . The method use of  claim 10 , wherein X 1  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 10-30 carbon atoms in the chain, wherein one or more of the carbon atoms in the chain is optionally replaced by (—O—) or (—NH—), and wherein the chain is optionally substituted on at least one carbon, —O— or —NH— with one or more substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 
   
   
       15 . The method of  claim 10 , wherein X 1  is a chain 18-24 atoms in length. 
   
   
       16 . The method of  claim 10 , wherein X 1  comprises a central diamine moiety having adjacent diglycolic acid molecules. 
   
   
       17 . The method of  claim 10 , wherein X 1  comprises at least one methylene. 
   
   
       18 . The method of  claim 10 , wherein R 1  is oxymorphone, α-oxymorphamine, a benzomorphan, etonitazine, fentanyl, or a compound of formula 100, 101, 102, 103, 104, or a derivative thereof. 
   
   
       19 . The method of  claim 10 , wherein R 2  is naltrindole or a compound of formula 201, 202, or 203, or a derivative thereof. 
   
   
       20 . The method of  claim 60 , wherein the conjugate has the following formula: 
     
       
         
         
             
             
         
       
     
     wherein n 1  is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
   
   
       21 . The method of  claim 20 , wherein n 1  is 5, 6, or 7. 
   
   
       22 . The method of  claim 60 , wherein administration of the conjugate is intravenous. 
   
   
       23 . The method of  claim 60 , wherein the conjugate is administered in combination with at least one additional therapeutic agent. 
   
   
       24 . A pharmaceutical composition comprising:
 a conjugate that comprises a mu opioid receptor agonist linked via a linker to a delta opioid receptor antagonist; and   a pharmaceutically acceptable carrier other than saline;   which composition is formulated for IV administration.   
   
   
       25 . A pharmaceutical composition comprising:
 a conjugate that comprises a mu opioid receptor agonist linked via a linker to a delta opioid receptor antagonist; and   a pharmaceutically acceptable carrier that comprises saline and at least one other pharmaceutically acceptable carrier;   which composition is formulated for intravenous administration.   
   
   
       26 . The composition of  claim 24 , wherein the conjugate has the formula:
   R 1 —X 1 —R 2      
     wherein
 R 1  is a mu opioid receptor agonist; 
 R 2  is a delta opioid receptor antagonist; and 
 X 1  is a linker. 
 
   
   
       27 . The pharmaceutical composition of  claim 26 , wherein X 1  comprises an amino acid. 
   
   
       28 . The pharmaceutical composition of  claim 26 , wherein X 1  comprises a peptide. 
   
   
       29 . The pharmaceutical composition of  claim 26 , wherein X 1  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 10-30 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NH—). 
   
   
       30 . The pharmaceutical composition of  claim 26 , wherein X 1  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 10-30 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NH—), and wherein the chain is optionally substituted on at least one carbon, —O— or —NH— with one or more substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 
   
   
       31 . The pharmaceutical composition of  claim 26 , wherein X 1  is a chain 18-24 atoms in length. 
   
   
       32 . The pharmaceutical composition of  claim 26 , wherein X 1  comprises a central diamine moiety having adjacent diglycolic acid molecules. 
   
   
       33 . The pharmaceutical composition of  claim 26 , wherein X 1  comprises at least one methylene. 
   
   
       34 . The pharmaceutical composition of  claim 26 , wherein R 1  is oxymorphone, oxymorphone, α-oxymorphamine, a benzomorphan, etonitazine, fentanyl, or a compound of formula 100, 101, 102, 103, 104, or a derivative thereof. 
   
   
       35 . The pharmaceutical composition of  claim 26 , wherein R 2  is naltrindole or a compound of formula 201, 202, or 203, or a derivative thereof. 
   
   
       36 . The pharmaceutical composition of  claim 24 , wherein the conjugate has the following formula: 
     
       
         
         
             
             
         
       
     
     wherein n 1  is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
   
   
       37 . The pharmaceutical composition of  claim 36 , wherein n 1  is 5, 6, or 7. 
   
   
       38 . A conjugate having the formula:
   R 1 —X 1 —R 2      
     wherein
 R 1  is a mu opioid receptor agonist; 
 R 2  is a delta opioid receptor antagonist; and 
 X 1  is a linker, provided that the conjugate is not a conjugate of the formula: 
 
     
       
         
         
             
             
         
       
     
     wherein n 1  is 2, 3, 4, 5, 6, or 7. 
   
   
       39 . A conjugate having the formula:
   R 1 —X 1 —R 2      
     wherein
 R 1  is a mu opioid receptor agonist that is not α-oxymorphamine; 
 R 2  is a delta opioid receptor antagonist; and 
 X 1  is a linker. 
 
   
   
       40 . The conjugate of  claim 38 , wherein R 1  is a benzomorphan, etonitazine, fentanyl, or a compound of formula 100, 101, 102, 103, 104, or a derivative thereof. 
   
   
       41 . A conjugate having the formula:
   R 1 —X 1 —R 2      
     wherein
 R 1  is a mu opioid receptor agonist; 
 R 2  is a delta opioid receptor antagonist that is not naltrindole; and 
 X 1  is a linker. 
 
   
   
       42 . The conjugate of  claim 38 , wherein R 2  is derivative or naltrindole or a compound of formula 201, 202, or 203, or a derivative thereof. 
   
   
       43 . A conjugate having the formula:
   R 1 —X 1 —R 2      
     wherein
 R 1  is a mu opioid receptor agonist; 
 R 2  is a delta opioid receptor antagonist; and 
 X 1  is a linker that is not 
 
     
       
         
         
             
             
         
       
     
     wherein n 1  is 2, 3, 4, 5, 6, or 7. 
   
   
       44 . The conjugate of  claim 38 , wherein X 1  comprises an amino acid. 
   
   
       45 . The conjugate of  claim 38 , wherein X 1  comprises a peptide. 
   
   
       46 . The conjugate of  claim 38 , wherein X 1  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 10-30 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NH—). 
   
   
       47 . The conjugate of  claim 38 , wherein X 1  is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 10-30 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NH—), and wherein the chain is optionally substituted on at least one carbon, —O— or —NH— with one or more substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 
   
   
       48 . The conjugate of  claim 38 , wherein X 1  is a chain 18-24 atoms in length. 
   
   
       49 . The conjugate of  claim 38 , wherein X 1  comprises a central diamine moiety having adjacent diglycolic acid molecules. 
   
   
       50 . The conjugate of  claim 38 , wherein X 1  comprises at least one methylene. 
   
   
       51 . The conjugate of  claim 41 , wherein R 1  is oxymorphone, α-oxymorphamine, a benzomorphan, etonitazine, fentanyl, or a compound of formula 100, 101, 102, 103, 104, or a derivative thereof. 
   
   
       52 . The conjugate of  claim 39 , wherein R 2  is naltrindole or a compound of formula 201, 202, or 203, or a derivative thereof. 
   
   
       53 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a conjugate as described in  claim 38 . 
   
   
       54 . A unit dosage form comprising a conjugate as described in  claim 38  and a pharmaceutically acceptable excipient. 
   
   
       55 - 59 . (canceled) 
   
   
       60 . A method for producing analgesia in a patient, comprising administering to the patient an effective amount of a conjugate that comprises a mu opioid receptor agonist linked via a linker to a delta opioid receptor antagonist, which administration is to a location outside the central nervous system of the patient. 
   
   
       61 . A method for producing analgesia while causing less inhibition of gastrointestinal (GI) transit than is caused by administration of a similar effective dosage of morphine in a patient, comprising administering to the patient an effective amount of a conjugate that comprises a mu opioid receptor agonist linked via a linker to a delta opioid receptor antagonist effective to cause analgesia while causing less inhibition of GI transit than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       62 . A method for producing analgesia while causing less dependence than is caused by administration of a similar effective dosage of morphine in a patient, comprising administering to the patient an effective amount of a conjugate that comprises a mu opioid receptor agonist linked via a linker to a delta opioid receptor antagonist effective to cause analgesia while causing less dependence than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       63 . A method for producing analgesia while causing less tolerance than is caused by administration of a similar effective dosage of morphine in a patient, comprising administering to the patient an effective amount of a conjugate that comprises a mu opioid receptor agonist linked via a linker to a delta opioid receptor antagonist effective to cause analgesia while causing less tolerance than is caused by administration of a similar effective dosage of morphine to a patient. 
   
   
       64 . (canceled)